rs55689103

Variant names:

• chr7-103593755-C-T
• rs55689103
• NM_005045.4:c.3839G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-103593755-C-T
• chr7-103593755-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):​c.3839G>A​(p.Gly1280Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,988 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 33)
  • Exomes 𝑓: 0.015 (204 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.57
• Publications: 16 publications found

Genes affected

RELN (HGNC:9957): (reelin) This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. This protein may be involved in schizophrenia, autism, bipolar disorder, major depression and in migration defects associated with temporal lobe epilepsy. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

RELN Gene-Disease associations (from GenCC):

• lissencephaly with cerebellar hypoplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Norman-Roberts syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• familial temporal lobe epilepsy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant epilepsy with auditory features

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ankylosing spondylitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010104984).
• BP6: Variant 7-103593755-C-T is Benign according to our data. Variant chr7-103593755-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0114 (1738/152274) while in subpopulation AMR AF = 0.0214 (328/15298). AF 95% confidence interval is 0.0195. There are 13 homozygotes in GnomAd4. There are 836 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.3839G>A	p.Gly1280Glu	missense	Exon 27 of 65	NP_005036.2
	RELN	NM_173054.3		c.3839G>A	p.Gly1280Glu	missense	Exon 27 of 64	NP_774959.1	P78509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.3839G>A	p.Gly1280Glu	missense	Exon 27 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.3839G>A	p.Gly1280Glu	missense	Exon 27 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.3839G>A	p.Gly1280Glu	missense	Exon 27 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1738 AN: 152156 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0102 AC: 2563 AN: 251166 AF XY: 0.0102

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00966

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0149 AC: 21802 AN: 1461714 Hom.: 204 Cov.: 32 AF XY: 0.0144 AC XY: 10479 AN XY: 727154

African (AFR) AF: 0.00251 AC: 84 AN: 33476

American (AMR) AF: 0.0105 AC: 471 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 432 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86252

European-Finnish (FIN) AF: 0.00354 AC: 189 AN: 53416

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5766

European-Non Finnish (NFE) AF: 0.0176 AC: 19572 AN: 1111904

Other (OTH) AF: 0.0151 AC: 909 AN: 60384

GnomAD4 genome AF: 0.0114 AC: 1738 AN: 152274 Hom.: 13 Cov.: 33 AF XY: 0.0112 AC XY: 836 AN XY: 74450

African (AFR) AF: 0.00327 AC: 136 AN: 41544

American (AMR) AF: 0.0214 AC: 328 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0168 AC: 1144 AN: 68026

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0143 Hom.: 49

Bravo AF: 0.0118

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0102 AC: 1238

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0166

EpiControl AF: 0.0183

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.97
MPC		0.77
ClinPred		0.013	T
GERP RS		6.1
Varity_R		0.31
gMVP		0.88
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55689103; hg19: chr7-103234202; COSMIC: COSV100635414;